Lissencephaly is a brain malformation characterized by the lack of gyri and the smooth cerebral surface, and in which abnormal layering of the neurons is observed. Lissencephaly patients display severe mental retardation, epileptic strokes, or the like, and their vital prognosis is poor. Lissencephaly patients generally die during their neonatal stage or during early childhood; some, however, live beyond their fifth birthday. The incidence of lissencephaly is about one in 15,000. The clinical diagnosis of lissencephaly is made by diagnostic imaging, such as MRI or CT. A medical specialist interprets images, and identifies gyri abnormalities to make a diagnosis.
About 60% of lissencephaly is presumably attributed to defective neuronal migration caused by heterozygous mutation of Pafah1b1 (LIS1) gene. Specifically, it is assumed that decreased LIS1 protein expression inhibits anterograde transport of cytoplasmic dynein, causing cytoplasmic dynein to localize at the centrosome. This then appears to cause defective neuronal migration, thereby resulting in abnormal layering of the central nervous system (i.e., onset of lissencephaly).
Although lissencephaly is an intractable disease for which an effective treatment has not yet been established, a recent breakthrough report is expected to lead to a treatment therefor (NPL 1). The report shows that, in experiments using cells with LIS1 gene heterozygous mutation (Lis1+/−), treatment of the cells with calpain inhibitor ALLN (Calpain Inhibitor I: the structure thereof is N-Acetyl-Leu-Leu-Nle-CHO (Calbiochem: 208719-25MG)) has increased LIS1 protein expression and restored neuronal migration. Moreover, the report suggests that intraperitoneal administration of ALLN to mice pregnant with Lis1+/− embryonic mice may provide symptomatic improvement in the embryonic mice with lissencephaly.
However, the report only indicates the possibility of ameliorating lissencephaly at the cellular level or embryonic level, and its actual application in clinical practice has remained difficult. This is because the common type of lissencephaly in humans is a sporadic type caused by mutation, and there is little chance that other family members will inherit the disease; thus, in most cases, the diagnosis of lissencephaly is made for the first time after birth, and postnatal treatment is accordingly required.
Additionally, ALLN is a highly toxic compound; thus, it has been difficult to use ALLN for the purpose of medical treatment.
Therefore, a therapeutic agent and method capable of even treating Lis1+/− newborn babies and infants who have been diagnosed with lissencephaly (i.e., capable of treating lissencephaly patients after birth) has been desired.
The compound represented by general formula (I) above and the method for preparing the compound are described in PTL 1, which also discloses that the compound is usable as a calpain inhibitor.